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Abstract:

Disclosed herein are pharmaceutical compositions comprising a plurality
of first beads each comprising: a core; a first layer comprising
pilocarpine or a pharmaceutically acceptable salt thereof; and a second
layer comprising a first polymer. Also disclosed are pharmaceutical
compositions comprising a plurality of second beads each comprising: a
core; and a first layer comprising tolterodine or a pharmaceutically
acceptable salt thereof. Further disclosed are pharmaceutical
formulations comprising: a) a plurality of the first beads; b) a
plurality of the second beads; or c) a plurality of the first beads and a
plurality of the second beads.

Claims:

1. A pharmaceutical composition comprising a plurality of first beads
each comprising: a core; a first layer comprising pilocarpine, or
cevimeline, or a pharmaceutically acceptable salt thereof; and a second
layer comprising a first polymer.

2. The pharmaceutical composition of claim 1, wherein the core comprises
a cellulose polymer, or silicon dioxide, or a sugar, selected from the
group consisting of glucose, sucrose, lactose, mannitol, xylitol, and
sorbitol.

3. The pharmaceutical composition of claim 1, wherein the core comprises
between about 10% to about 50% of the total weight of the
finally-formulated bead.

4. The pharmaceutical composition of claim 1, wherein the first layer
comprises between about 1% to about 50% of the total weight of the bead.

6. The pharmaceutical composition of claim 1, wherein the second layer
further comprises an insoluble film-forming polymer selected from the
group consisting of ethylcellulose, cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate, insoluble gums, a
polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetate
phthalate.

7. The pharmaceutical composition of claim 1, wherein the bead further
comprises a de-tackifier or a glidant selected from the group consisting
of talc, glyceryl monostearate, calcium stearate, and magnesium stearate.

8. The pharmaceutical composition of claim 1, wherein the bead further
comprises a plasticizer selected from the group consisting of a
phthalate-based plasticizer, a trimellitate, an adipate-based
plasticizer, a sebacate-based plasticizer, an organophosphate, a maleate,
a sulfonamide, a glycols or polyether, an acetylated monoglyceride, and
an alkyl citrate.

10. A pharmaceutical composition comprising a plurality of second beads
each comprising: a core; and a first layer comprising a muscarinic
antagonist or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 10, wherein the muscarinic
antagonist is selected from the group consisting of tolterodine,
5-hydroxymethyl tolterodine, fesoterodine, oxybutynin, solifenacin,
darifenacin, trospium, imidafenacin, propiverine, and dicyclomine.

12. The pharmaceutical composition of claim 10, wherein the core
comprises a cellulose polymer, or silicon dioxide, or a sugar, selected
from the group consisting of glucose, sucrose, lactose, mannitol,
xylitol, and sorbitol.

13. The pharmaceutical composition of claim 10, wherein the core
comprises between about 10% to about 90% of the total weight of the
finally-formulated bead.

14. The pharmaceutical composition of claim 10, wherein the first layer
comprises between about 1% to about 50% of the total weight of the bead.

16. The pharmaceutical composition of claim 10, wherein the bead further
comprises: a de-tackifier or a glidant selected from the group consisting
of talc, glyceryl monostearate, calcium stearate, and magnesium stearate;
and a plasticizer selected from the group consisting of a phthalate-based
plasticizer, a trimellitate, an adipate-based plasticizer, a
sebacate-based plasticizer, an organophosphate, a maleate, a sulfonamide,
a glycols or polyether, an acetylated monoglyceride, and an alkyl
citrate.

17. The pharmaceutical composition of claim 10, further comprising a
second layer, which comprises a soluble-film forming polymer.

19. A pharmaceutical formulation comprising: a) a plurality of the first
beads of claim 1; b) a plurality of the second beads of claim 10; or c) a
plurality of the first beads of claim 1 and a plurality of the second
beads of claim 10.

20. The pharmaceutical formulation of claim 19, comprising: a)
pilocarpine or cevimeline, or a pharmaceutically acceptable salt thereof,
in a dose between 0.5-50 mg; and b) a muscarinic antagonist, or a
pharmaceutically acceptable salt thereof, in a dose between 0.1-100 mg.

Description:

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application
No. 61/320,202, filed Apr. 1, 2010, by Mehdi Paborji, and entitled
"PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF OVERACTIVE BLADDER,"
which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention is in the field of pharmaceutical
formulations, and in particular formulations comprising pilocarpine or
cevimeline, formulations comprising a muscarinic antagonist, and
formulations comprising a combination of pilocarpine or cevimeline and a
muscarinic antagonist.

BACKGROUND OF THE DISCLOSURE

[0003] Muscarinic receptor antagonists, such as tolterodine, are known for
the treatment of overactive bladder. However, an adverse side effect of
these treatments is severe dry mouth. This side effect causes significant
patient discomfort and reduces compliance greatly. Previous work has
shown that the combination of tolterodine or oxybutynin with pilocarpine,
a muscarinic receptor agonist that increases saliva formation, can
significantly reduce the incidents of dry mouth while not affecting the
efficacy of the muscarinic receptor antagonist. See, for example, U.S.
Pat. Nos. 7,666,894, 7,678,821, and 7,781,472, and U.S. Application
Publication Nos. 2009/0275629 and 2010/0152263, all of which are
incorporated herein by reference in their entirety.

[0004] As discussed in the aforementioned publications, one cannot simply
take a muscarinic antagonist and pilocarpine or cevimeline and expect to
obtain the desired clinical efficacy. The timing of the administration of
the muscarinic agonist vis-a-vis the administration of the muscarinic
antagonist has to be adjusted properly so that the maximum increase in
saliva formation due to the administration of the muscarinic agonist is
reached at the same time as the maximum dry mouth experienced due to the
administration of the muscarinic antagonist. Taking two tablets at two
different times, where the time difference between the two
administrations has to be exact, is inconvenient, cumbersome, and reduces
patient compliance. Therefore, a single pharmaceutical formulation is
needed where the desired time delay and release profile are incorporated.

SUMMARY OF THE INVENTION

[0005] Disclosed herein are pharmaceutical compositions comprising a
plurality of first beads each comprising: a core; a first layer
comprising pilocarpine, cevimeline, or a pharmaceutically acceptable salt
thereof; and a second layer comprising a first polymer. Also disclosed
are pharmaceutical compositions comprising a plurality of second beads
each comprising: a core; and a first layer comprising a muscarinic
antagonist or a pharmaceutically acceptable salt thereof. Further
disclosed are pharmaceutical formulations comprising: a) a plurality of
the first beads; b) a plurality of the second beads; or c) a plurality of
the first beads and a plurality of the second beads.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0006] Aspects of the present disclosure include pharmaceutical
formulations comprising a muscarinic antagonist in an immediate release
formulation. Once ingested by a subject, the muscarinic antagonist in
these formulations begins to release into the gut to be systemically
absorbed into the blood stream. Other aspects of the present disclosure
include pharmaceutical formulations comprising pilocarpine or cevimeline,
both of which are muscarinic agonists. The muscarinic agonist of the
pharmaceutical formulations is present in a delayed immediate release
formulation. Once ingested, the muscarinic agonist is not released for
some time. But once the muscarinic agonist begins to be released, it is
released immediately.

[0007] In some embodiments, the muscarinic antagonist of the formulations
disclosed herein is a compound that is used for the treatment of
overactive bladder. In certain embodiments, the muscarinic antagonist is
selected from the group consisting of tolterodine, 5-hydroxymethyl
tolterodine, fesoterodine, oxybutynin, solifenacin, darifenacin,
trospium, imidafenacin, propiverine, and dicyclomine.

[0008] In the context of the present disclosure, "immediate release" or
"released immediately" means that at least about 70% of the ingested
active pharmaceutical ingredient in the dosage form is released from the
pharmaceutical formulation within about 30-60 minutes of the ingestion of
the dosage form. By "not released" or "delayed released" it is meant that
less than 20% of the ingested active pharmaceutical ingredient in the
dosage form is released from the pharmaceutical formulation by the time
the delay is concluded and the release becomes immediate.

[0009] Throughout the present disclosure the term "about" a certain value
means that a range of value±10%, and preferably a range of
value±5%, is contemplated. Thus, for example, having about 70% of the
active pharmaceutical ingredient (API) includes API being present between
63% and 87%, and preferably between 66.5% and 73.5%; or by way of another
example, "about 45 minutes" means that the contemplated value is between
40.5 minutes and 49.5 minutes, and preferably between 42.75 minutes and
47.25 minutes.

[0010] Disclosed herein are beads, or multiparticulate systems, comprising
a muscarinic agonist, i.e., pilocarpine or cemiveline, and other beads
comprising a muscarinic antagonist. Contemplated within the scope of the
present disclosure are pharmaceutical compositions comprising muscarinic
agonist beads only, muscarinic antagonist beads only, or compositions
comprising both muscarinic agonist and muscarinic antagonist beads. The
muscarinic agonist-only or muscarinic antagonist-only beads can be
administered individually or in combination with beads or other
pharmaceutical formulations comprising other active ingredients.

Muscarinic Agonist Beads

[0011] Thus, in one aspect, disclosed herein are pharmaceutical
compositions comprising a plurality of first beads each comprising:

[0012] a core;

[0013] a first layer comprising a muscarinic agonist, i.e., pilocarpine or
cemiveline, or a pharmaceutically acceptable salt thereof; and

[0014] a second layer comprising a first polymer.

[0015] In some embodiments, the core comprises a polymer. In certain
embodiments, the core polymer is a cellulose polymer. In some of these
embodiments, the cellulose polymer is microcrystalline cellulose. In
other embodiments, the core comprises a sugar. In certain embodiments,
the sugar is selected from the group consisting of glucose, sucrose,
lactose, mannitol, maltodextrine, xylitol, and sorbitol. In further
embodiments, the core comprises silicon dioxide.

[0016] In some embodiments, the core is obtained commercially. An example
of commercially available beads to be used as core for the beads
disclosed herein includes, but is not limited to, sugar spheres (for
example, Paular spheres), Cellets® cores, such as Cellets® 100,
Cellets® 200, Cellets® 350, Cellets® 500, Cellets® 700,
or Cellets® 1000 (Glatt Air Techniques Inc., Ramsey N.J.). In other
embodiments, the core is prepared de novo, for example by preparing a
polymer mixture, extruding the mixture, and spheronizing the extruded
mixture to form spherical or semi-spherical beads. In some embodiments,
the beads are swellable such that their exposure to aqueous media causes
them to swell and release the active ingredient rapidly and efficiently.

[0017] In some embodiments, the core comprises between about 10% to about
50% of the total weight of the finally-formulated bead. In some
embodiments, the core comprises between about 15% to about 40% of the
total weight of the finally-formulated bead. In some embodiments, the
core comprises between about 20% to about 30% of the total weight of the
finally-formulated bead. In some embodiments, the core comprises about
20% of the total weight of the finally-formulated bead. In some
embodiments, the core comprises about 25% of the total weight of the
finally-formulated bead.

[0018] In some embodiments, a solution of the muscarinic agonist, a free
base thereof or a pharmaceutically acceptable salt thereof, is prepared
and then sprayed onto the core and then dried. The act of spraying and
drying causes a layer (the first layer) of the API (i.e., pilocarpine or
cevimeline) to form over the bead. In some embodiments, the solution
comprises a polymer that causes the API to more efficiently adhere to the
core. The amount of the API present in the dosage form can be controlled
by controlling the thickness of the first layer and/or by the
concentration of the solution comprising the API. The thicker the first
layer, or the more concentrated the API solution, the more API is present
in the dosage form. Once the first layer is exposed to aqueous media, for
example gastric or intestinal juice, the pilocarpine contained therein
immediately dissolves into the aqueous medium. Methods of applying the
first layer uniformly onto the core are well-known in the art.

[0019] In some embodiments, the first layer comprises between about 1% to
about 50% of the total weight of the bead. In some embodiments, the first
layer comprises between about 2% to about 40% of the total weight of the
bead. In some embodiments, the first layer comprises between about 5% to
about 30% of the total weight of the bead. In some embodiments, the first
layer comprises between about 7% to about 25% of the total weight of the
bead. In some embodiments, the first layer comprises between about 8% to
about 15% of the total weight of the bead. In some embodiments, the first
layer comprises about 8% of the total weight of the bead. In some
embodiments, the first layer comprises about 10% of the total weight of
the bead. In some embodiments, the first layer comprises about 12% of the
total weight of the bead. In some embodiments, the first layer comprises
about 15% of the total weight of the bead.

[0020] In some embodiments, pilocarpine or cevimeline is present as the
free base. In other embodiments, pilocarpine or cevimeline is present as
a pharmaceutically acceptable salt. The term "pharmaceutically acceptable
salt" refers to a formulation of a compound that does not abrogate the
biological activity and properties of the compound. Pharmaceutical salts
can be obtained by reacting a compound of the invention with inorganic
acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts
can be obtained by reacting a compound of the invention with inorganic
acids such as tartaric acid, oxalic acid, "carbonic acid" to form the
bicarbonate or carbonate salt of the compound, acetic acid, formic acid,
benzoic acid, and the like. Pharmaceutical salts can also be obtained by
reacting a compound of the invention with a base to form a salt such as
an ammonium salt, an alkali metal salt, such as a sodium or a potassium
salt, an alkaline earth metal salt, such as a calcium or a magnesium
salt, a salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with
amino acids such as arginine, lysine, and the like. In some embodiments,
the pilocarpine is pilocarpine HCl or pilocarpine nitrate.

[0021] Once the API (pilocarpine, cevimeline, or a salt thereof) is coated
onto the bead, the bead is coated with a second layer. The second layer
delays the exposure of the first layer to the aqueous media. The second
layer comprises at least one polymer, the first polymer.

[0022] In some embodiments, the first polymer comprises a soluble
film-forming polymer. By "soluble" it is meant that the polymer is
soluble in aqueous media, which means that at least about 50% of the
polymer has dissolved within one hour after exposure to the aqueous
media. It is understood that some polymers disperse in aqueous solutions.
This dispersion is not the same as dissolving. For a compound or polymer
to be soluble, there needs to be a concentration of the compound or
polymer in the solvent having solute-solvent interactions, as understood
in the chemical arts.

[0023] In some embodiments, the first polymer is a sugar or a
polysaccharide. In some of these embodiments, the sugar or polysaccharide
is selected from the group consisting of cellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, maltodextrin,
sucrose, modified starch, a salt of alginic acid, soluble gums, and
carageenan. In other embodiments, the first polymer is
polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone (PVPP).

[0024] In some embodiments, the soluble-forming polymer is a mixture of
two or more polymers. In some embodiments, the mixture comprises
hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC).

[0025] In some embodiments, hydroxypropylmethylcellulose is present in
between about 1% to about 50% of the total weight of the bead. In some
embodiments, hydroxypropylmethylcellulose is present in between about 2%
to about 40% of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in between about 5% to about 30%
of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in between about 7% to about 25%
of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in between about 8% to about 15%
of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 8% of the total weight
of the bead. In some embodiments, hydroxypropylmethylcellulose is present
in about 10% of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 12% of the total weight
of the bead. In some embodiments, hydroxypropylmethylcellulose is present
in about 15% of the total weight of the bead.

[0026] In some embodiments, hydroxypropylcellulose is present in between
about 1% to about 90% of the total weight of the bead. In some
embodiments, hydroxypropylcellulose is present in between about 5% to
about 40% of the total weight of the bead. In some embodiments,
hydroxypropylcellulose is present in between about 10% to about 30% of
the total weight of the bead. In some embodiments, hydroxypropylcellulose
is present in between about 15% to about 25% of the total weight of the
bead. In some embodiments, hydroxypropylcellulose is present in between
about 20% to about 25% of the total weight of the bead. In some
embodiments, hydroxypropylcellulose is present in about 21.50% of the
total weight of the bead. In some embodiments, hydroxypropylcellulose is
present in about 22.25% of the total weight of the bead. In some
embodiments, hydroxypropylcellulose is present in about 22.75% of the
total weight of the bead. In some embodiments, hydroxypropylcellulose is
present in about 24.50% of the total weight of the bead.

[0027] In some embodiments, the second layer further comprises an
insoluble film-forming polymer. By "insoluble" it is meant that the
polymer is insoluble in aqueous media, which means that at most about 10%
of the polymer has dissolved within one hour after exposure to the
aqueous media. The presence of the insoluble film-forming polymer in the
second layer causes greater delay in the exposure of the first layer to
the aqueous media. The insoluble film-forming polymer and the soluble
film-forming polymer form a matrix where upon exposure to the aqueous
media the soluble polymer dissolves leaving pores in a network of
insoluble polymer through which pores the API in the first layer leaches
out into the aqueous media.

[0028] In some embodiments, the insoluble film-forming polymer is a
polysaccharide. In some of these embodiments, the polysaccharide is
selected from the group consisting of ethylcellulose, cellulose acetate
phthalate, hydroxypropylmethylcellulose phthalate, and insoluble gums. In
other embodiments, the insoluble film-forming polymer is selected from
the group consisting of a polymethacrylate, a polyvinyl alcohol, shellac,
and polyvinyl acetate phthalate.

[0029] In some embodiments, ethylcellulose is present in between about 1%
to about 90% of the total weight of the bead. In some embodiments,
ethylcellulose is present in between about 5% to about 40% of the total
weight of the bead. In some embodiments, ethylcellulose is present in
between about 10% to about 30% of the total weight of the bead. In some
embodiments, ethylcellulose is present in between about 15% to about 25%
of the total weight of the bead. In some embodiments, ethylcellulose is
present in between about 20% to about 25% of the total weight of the
bead. In some embodiments, ethylcellulose is present in about 21.50% of
the total weight of the bead. In some embodiments, ethylcellulose is
present in about 22.25% of the total weight of the bead. In some
embodiments, ethylcellulose is present in about 22.75% of the total
weight of the bead. In some embodiments, ethylcellulose is present in
about 24.50% of the total weight of the bead.

[0030] In some embodiments, the second layer comprises
hydroxypropylcellulose and ethylcellulose. In some embodiments, the ratio
of hydroxypropylcellulose to ethylcellulose is between about 5:1 to about
1:5 by weight. In some embodiments, the ratio of hydroxypropylcellulose
to ethylcellulose is between about 4:1 to about 1:4 by weight. In some
embodiments, the ratio of hydroxypropylcellulose to ethylcellulose is
between about 3:1 to about 1:3 by weight. In some embodiments, the ratio
of hydroxypropylcellulose to ethylcellulose is between about 2:1 to about
1:2 by weight. In some embodiments, the ratio of hydroxypropylcellulose
to ethylcellulose is about 1:1 by weight.

[0031] In some embodiments, the first bead further comprises a
de-tackifier or a glidant. In some embodiments, the de-tackifier or
glidant is an inert mineral. An inert mineral is a mineral, i.e., an
inorganic compound or salt, that is pharmaceutically acceptable and does
not interfere with the pharmacological action of the therapeutic
compound. In some embodiments, the inert mineral is a mineral of
magnesium. In other embodiments, the mineral of magnesium is magnesium
silicate. In certain embodiments, the de-tackifier or glidant is selected
from the group consisting of talc, a monoglyceride, a diglyceride,
glyceryl monostearate, calcium stearate, and magnesium stearate.

[0032] In some embodiments, the de-tackifier or glidant is present in
between about 1% to about 50% of the total weight of the bead. In some
embodiments, the de-tackifier or glidant is present in between about 2%
to about 40% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in between about 3% to about 20% of
the total weight of the bead. In some embodiments, the de-tackifier or
glidant is present in between about 4% to about 10% of the total weight
of the bead. In some embodiments, the de-tackifier or glidant is present
in about 4% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 4.5% of the total weight of
the bead. In some embodiments, the de-tackifier or glidant is present in
about 5% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 5.5% of the total weight of
the bead. In some embodiments, the de-tackifier or glidant is present in
about 6% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 6.5% of the total weight of
the bead.

[0034] In some embodiments, the first bead further comprises a
plasticizer. In some embodiments, the plasticizer is selected from the
group consisting of a phthalate-based plasticizer, a trimellitate, an
adipate-based plasticizer, a sebacate-based plasticizer, an
organophosphate, a maleate, a sulfonamide, a glycols or polyether, an
acetylated monoglyceride, and an alkyl citrate.

[0036] In some embodiments, the plasticizer is present in between about 1%
to about 50% of the total weight of the bead. In some embodiments, the
plasticizer is present in between about 2% to about 40% of the total
weight of the bead. In some embodiments, the plasticizer is present in
between about 3% to about 20% of the total weight of the bead. In some
embodiments, the plasticizer is present in between about 4% to about 10%
of the total weight of the bead. In some embodiments, the plasticizer is
present in about 4% of the total weight of the bead. In some embodiments,
the plasticizer is present in about 4.5% of the total weight of the bead.
In some embodiments, the plasticizer is present in about 5% of the total
weight of the bead. In some embodiments, the plasticizer is present in
about 5.5% of the total weight of the bead. In some embodiments, the
plasticizer is present in about 6% of the total weight of the bead. In
some embodiments, the plasticizer is present in about 6.5% of the total
weight of the bead.

[0037] In some embodiments, the weight of the second layer is between
about 50% to about 300% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is between about 75% to about 250% of the weight of the bead
prior to the application of the second layer. In some embodiments, the
weight of the second layer is about 75% of the weight of the bead prior
to the application of the second layer. In some embodiments, the weight
of the second layer is about 100% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is about 125% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is about 150% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is about 175% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is about 200% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is about 225% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of the
second layer is about 250% of the weight of the bead prior to the
application of the second layer.

Muscarinic Antagonist Beads

[0038] In another aspect, disclosed herein are pharmaceutical compositions
comprising a plurality of second beads each comprising: [0039] a core;
and [0040] a first layer comprising a muscarinic antagonist or a
pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the muscarinic antagonist is present as the
free base. In other embodiments, the muscarinic antagonist is present as
a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are
defined above. In some embodiments, the muscarinic antagonist is selected
from the group consisting of tolterodine, 5-hydroxymethyl tolterodine,
fesoterodine, oxybutynin, solifenacin, darifenacin, trospium,
imidafenacin, propiverine, and dicyclomine. In some embodiments, the
tolterodine is tolterodine tartrate. In other embodiments, the oxybutynin
is oxybutynin chloride.

[0042] In some embodiments, the core of the plurality of the second beads
is comprised of the same material as the core of the plurality of the
first beads, discussed above.

[0043] In some embodiments, the core comprises between about 10% to about
90% of the total weight of the finally-formulated bead. In some
embodiments, the core comprises between about 25% to about 85% of the
total weight of the finally-formulated bead. In some embodiments, the
core comprises between about 40% to about 80% of the total weight of the
finally-formulated bead. In some embodiments, the core comprises about
80% of the total weight of the finally-formulated bead. In some
embodiments, the core comprises about 75% of the total weight of the
finally-formulated bead. In some embodiments, the core comprises about
85% of the total weight of the finally-formulated bead.

[0044] In some embodiments, a solution of the API (i.e., the muscarinic
antagonist), or a pharmaceutically acceptable salt thereof, is prepared
and then sprayed onto the core and then dried. The act of spraying and
drying causes a layer (the first layer) of the API to form over the bead.
In some embodiments, the solution comprises a polymer that causes the API
to more efficiently adhere to the core. The amount of the API present in
the dosage form can be controlled by controlling the thickness of the
first layer. The thicker the first layer the more API is present in the
dosage form. Once the first layer is exposed to aqueous media, for
example gastric or intestinal juice, the tolterodine contained therein
immediately dissolves into the aqueous medium. Methods of applying the
first layer uniformly onto the core are well-known in the art.

[0045] In some embodiments, the first layer comprises between about 1% to
about 50% of the total weight of the bead. In some embodiments, the first
layer comprises between about 2% to about 40% of the total weight of the
bead. In some embodiments, the first layer comprises between about 4% to
about 25% of the total weight of the bead. In some embodiments, the first
layer comprises between about 5% to about 15% of the total weight of the
bead. In some embodiments, the first layer comprises between about 5.5%
to about 10% of the total weight of the bead. In some embodiments, the
first layer comprises about 6% of the total weight of the bead. In some
embodiments, the first layer comprises about 6.5% of the total weight of
the bead. In some embodiments, the first layer comprises about 7% of the
total weight of the bead. In some embodiments, the first layer comprises
about 8% of the total weight of the bead.

[0046] In some embodiments, the first layer comprises a soluble
film-forming polymer, as defined above.

[0047] In some embodiments, hydroxypropylmethylcellulose is present in
between about 1% to about 50% of the total weight of the bead. In some
embodiments, hydroxypropylmethylcellulose is present in between about 2%
to about 40% of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in between about 5% to about 30%
of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in between about 7% to about 25%
of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in between about 8% to about 15%
of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 8% of the total weight
of the bead. In some embodiments, hydroxypropylmethylcellulose is present
in about 10% of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 12% of the total weight
of the bead. In some embodiments, hydroxypropylmethylcellulose is present
in about 15% of the total weight of the bead.

[0048] In some embodiments, the second bead further comprises a
de-tackifier or a glidant, as defined above. In some embodiments, the
de-tackifier or glidant is present in between about 1% to about 50% of
the total weight of the bead. In some embodiments, the de-tackifier or
glidant is present in between about 2% to about 40% of the total weight
of the bead. In some embodiments, the de-tackifier or glidant is present
in between about 3% to about 20% of the total weight of the bead. In some
embodiments, the de-tackifier or glidant is present in between about 4%
to about 10% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 3% of the total weight of the
bead. In some embodiments, the de-tackifier or glidant is present in
about 3.5% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 4% of the total weight of the
bead. In some embodiments, the de-tackifier or glidant is present in
about 4.5% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 5% of the total weight of the
bead. In some embodiments, the de-tackifier or glidant is present in
about 5.5% of the total weight of the bead.

[0050] In some embodiments, the second bead further comprises a
plasticizer, as defined above. In some embodiments, the plasticizer is
polyethylene glycol. In certain embodiments, the polyethylene glycol is
PEG 400.

[0051] In some embodiments, the plasticizer is present in between about
0.1% to about 50% of the total weight of the bead. In some embodiments,
the plasticizer is present in between about 0.1% to about 40% of the
total weight of the bead. In some embodiments, the plasticizer is present
in between about 0.1% to about 5% of the total weight of the bead. In
some embodiments, the plasticizer is present in between about 0.2% to
about 2% of the total weight of the bead. In some embodiments, the
plasticizer is present in about 0.1% of the total weight of the bead. In
some embodiments, the plasticizer is present in about 0.15% of the total
weight of the bead. In some embodiments, the plasticizer is present in
about 0.2% of the total weight of the bead. In some embodiments, the
plasticizer is present in about 0.25% of the total weight of the bead. In
some embodiments, the plasticizer is present in about 0.3% of the total
weight of the bead. In some embodiments, the plasticizer is present in
about 0.35% of the total weight of the bead. In some embodiments, the
plasticizer is present in about 0.4% of the total weight of the bead.

[0052] In some embodiments, the second beads further comprise a second
layer. In some embodiments, the second layer comprises ingredients
similar to the first layer, discussed above, except that the second layer
does not have any API. In some embodiments, the first layer and the
second layer have identical set of ingredients, whereas in other
embodiments, the first and second layers have different combination of
ingredients.

Pharmaceutical Formulations

[0053] In another aspect, disclosed herein are pharmaceutical formulations
comprising one of the following combinations of the above beads: a) a
plurality of the first beads; b) a plurality of the second beads; or c) a
plurality of the first beads and a plurality of the second beads.

[0054] The disclosed pharmaceutical formulations contain sufficient number
of beads to provide a single administrable dose to a subject. In some
embodiments, a single administrative dose for the muscarinic agonist is
between 0.5-50 mg. In certain embodiments, a single administrable dose of
pilocarpine is selected from the group consisting of 3 mg, 4 mg, 5 mg, 6
mg, 10 mg, 11 mg, and 12 mg. In other embodiments, a single administrable
dose of cevimeline is selected from the group consisting of 5 mg, 10 mg,
15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, and 60 mg. In certain
embodiments, a single administrable dose for the muscarinic antagonist is
between 0.1-100 mg. In certain embodiments, a single administrative dose
is selected from the group consisting of 0.1 mg, 0.2 mg, 0.4 mg, 0.5 mg,
1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 10 mg, 12 mg, 15
mg, 30 mg, and 60 mg.

[0055] In some embodiments, the pharmaceutical formulations are in the
form of capsules. The capsules may include push-fit capsules made of
gelatin, push-fit capsules, for example those made of
hydroxypropylmethylcellulose, banded push-fit capsules, as well as soft,
sealed capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol.

[0056] In some embodiments, the pharmaceutical formulations are in the
form of dose sipping straws. In some embodiments, the beads are filled
into a straw and a patient then drinks liquid through the straw, and
through the process of drinking, the liquid pulled through the straw
brings the beads into the mouth along with the liquid.

[0057] In some embodiments, the pharmaceutical formulations are in the
form of dry sachets. In some embodiments, the beads are sprinkled onto
food or mixed into a drink from dry sachet, and taken orally. For the
dosage to be effective, the disclosed beads are filled into a sachet
pouch, along with additional excipients needed to form a readily
dispersible suspension. When the pouch is opened and the contents are
poured over food or into a drink, the beads and additional excipients are
mixed with the food or the drink, and form a palatable dispersion that is
ingested by the subject. Excipients, such as salivants and glidants, are
added for the contents to be easily swallowed with a minimum of chewing
so that the coatings are not broken in the mouth.

[0058] In some embodiments, the pharmaceutical formulations are in the
form of ready-to-use sachets. In some embodiments, the beads are premixed
with an edible, high viscosity food substance (for example, yogurt, or
energy gel), and the entire contents of the package is taken orally.
Excipients, such as salivants and glidants, are added for the contents to
be easily swallowed with a minimum of chewing so that the coatings are
not broken in the mouth.

[0059] In some embodiments, the pharmaceutical formulations are in the
form of suspensions. In some embodiments, the suspensions comprise
ingredients such as glycerin, microcrystalline cellulose, carboxymethyl
cellulose sodium, sorbitol solution, xanthan gum, and the like, and
various colorings and flavorings to make the suspension palatable for
pediatric or geriatric use.

[0060] In some embodiments, the first beads disclosed above, having
pilocarpine or a pharmaceutically acceptable salt thereof, and the first
and second layers, are coated with a third layer comprising tolterodine,
or a pharmaceutically acceptable salt thereof. The third layer is the
same as, or similar to, the first layer of the second beads discussed
above. In certain embodiments, the tolterodine-coated first bead is
further coated with a fourth layer, which is the same as, or similar to,
the second layer of the second beads discussed above.

EXAMPLES

Example 1

Materials Used in the Bead Manufacturing Process

[0061] The raw materials listed in Table 1 were used in the production of
the pilocarpine and tolterodine beads.

[0063] This method describes the procedure for the determination of the
dissolution rate of the pilocarpine HCl and tolterodine tartrate
combination formulations by using a reverse-phase, gradient,
high-pressure liquid chromatography (HPLC) method, using techniques
well-known in the art.

[0064] Stock solutions of pilocarpine HCl and tolterodine tartrate were
prepared as working standards. Beads containing pilocarpine HCl and
tolterodine tartrate are separately mixed with a fixed volume of 0.1 N
HCl. At fixed time points after the mixing has begun, aliquots of the
dissolution mixtures are injected into HPLC followed by several aliquots
of the working standards. The amounts of released (dissolved) tolterodine
and pilocarpine entities of formulations were calculated using the
corresponding peak areas of tolterodine and pilocarpine.

[0065] A USP 2 Paddles method with the following conditions was employed
to determine dissolution of various formulations.

[0066] Dissolution media: 0.1 N HCl

[0067] Agitation Rate: 50 RPM

[0068] Vessel Temp: 37° C.±0.5° C.

[0069] Sample Volume: 1.0 mL

[0070] Disso Volume: 500 mL

Example 3

Bead Formation

[0071] Beads were produced by drug layering microcrystalline cellulose
beads with aqueous, cellulosic coating systems containing pilocarpine HCl
or tolterodine tartrate. The beads were formulated into single dose
units. The coating formulations are displayed in Tables 3 and 4 below:

[0072] Both coating solutions were applied to the Microcrystalline
Cellulose (MCC) Pellets using a Vector FLM-1 fluid bed with a Wurster
coating configuration. Beads were hand-filled into size 2 gelatin
capsules and tested for dissolution using the procedure of Example 2. The
dissolution data of the drug layered beads are shown in Tables 5 and 6:

[0073] Both types of drug layered beads were top-coated. The tolterodine
beads were coated with a thin, immediate release HPMC based coating
system to ensure no tolterodine tartrate was lost from erosion. The
topcoat for the pilocarpine HCl beads was developed in rounds 2-5 of
development.

Example 4

Bead Formation

[0074] The development in this example focused on the use of several types
and grades of cellulosic polymers in order to form a semi-permeable
barrier that would delay release. All coatings applied were at relatively
low weight gains, no higher than 50%. It was determined that the
application of high weight gains produced the desired delayed release
profile. The formulations and release profiles are summarized in Table 7
below:

[0076] In this example, swellable beads containing pilocarpine HCl were
produced. First, placebo beads were produced in order to compare two
common super-disintegrants. The criterion for super-disintegrant
selection was volume increase as the beads were placed in 0.1 N HCl. The
formulations and results are below in Table 9:

[0077] Two swellable pilocarpine HCl bead formulations were produced, with
differing quantities of pilocarpine. These beads were then each coated
with the same ethylcellulose based coating system and tested for
dissolution. The formulations and results are set forth below in Table
10.

[0079] This example focused on coating drug-layered microcrystalline
cellulose cores with cellulosic polymers to high weight gains (up to
200%). The first coating formulation consisted of a soluble polymer,
hydroxypropylcellulose (HPC), which forms a hydrogel that delays release.
The second formulation consisted of a 1:1 ratio of HPC and
ethylcellulose. The thickness of both types of films directly correlated
to the delay in release of pilocarpine HCl. The formulations for each
prototype are shown below in Table 12.

[0080] Beads having the following weight gains were produced: 75%, 100%,
125%, 150%, 175%, and 200%. This set of beads exhibited a wide range of
lag times, followed by immediate release. The delay in release is
controlled by the thickness of the film. The dissolution data, obtained
using the procedure of Example 2, are shown in Tables 13 and 14.

[0081] Cevimeline beads are produced in substantially the same manner as
pilocarpine beads, as described above, except that cevimeline is used
instead of pilocarpine.

Example 7

Muscarinic Antagonist Bead Formation

[0082] Beads containing a muscarinic antagonist selected from the group
consisting of the muscarinic antagonist is selected from the group
consisting of 5-hydroxymethyl tolterodine, fesoterodine, oxybutynin,
solifenacin, darifenacin, trospium, imidafenacin, propiverine, and
dicyclomine are prepared in substantially the same manner as tolterodine
beads, as described above, except that the specific muscarinic antagonist
is used instead of tolterodine.